Pharmacokinetics and Safety of TIN816 in Patients With Sepsis-associated Acute Kidney Injury

• ClinicalTrials.gov Identifier: NCT05507437
• Recruitment Status: Recruiting
• First Posted: August 19, 2022
• Last Update Posted: May 22, 2023
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

Brief Summary:

The purpose of this study is to characterize the pharmacokinetic (PK) and pharmacodynamic (PD) profile and to evaluate the safety and tolerability of TIN816 in hospitalized adult participants in an intensive care setting with a diagnosis of sepsis-associated acute kidney injury (SA-AKI).

Condition or disease	Intervention/treatment	Phase
Acute Kidney Injury Due to Sepsis	Biological: TIN816 70 mg lyophilisate powder; Other: Placebo	Phase 2

Detailed Description:

This is a multicenter, participant and investigator-blinded, randomized, placebo-controlled study to characterize PK/PD profile and to evaluate the safety and the tolerability of TIN816. The study will enroll hospitalized adult participants with a diagnosis of sepsis and acute kidney injury (AKI). Approximately 20 participants will be randomized in the study. The study consists of a screening period (24-48 hours), a treatment period (day 1), and post-treatment period (days 2 to 90).

Screening will take place during hospitalization in a intensive care unit (ICU) (or intermediate/high dependency unit (HDU care) where potential participants will undergo screening to assess the presence of sepsis and AKI. Pre-identified participants will provide informed consent and undergo screening assessments to determine eligibility. Potential study candidates will be hospitalized patients with a diagnosis of sepsis based on Sepsis 3 criteria with suspected or confirmed infection and SOFA score ≥ 2 after excluding the renal component, and a diagnosis of AKI stage 1 or greater. At Treatment Day 1, participants who meet eligibility criteria at screening and baseline will be randomized in a 3:1 ratio to treatment with TIN816 or placebo by intravenous infusion in a participant and investigator-blinded fashion.

Treatment day 1 is followed by a 90 day post-treatment period for pharmocokinetic, pharmacodynamic, safety and tolerability assessments.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Participant and Investigator-blinded, Randomized, Placebo-controlled Phase 2a Study to Investigate the Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of TIN816 in Patients With Sepsis-associated Acute Kidney Injury
• Actual Study Start Date: November 22, 2022
• Estimated Primary Completion Date: December 4, 2023
• Estimated Study Completion Date: December 4, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: TIN816; Administered as an intravenous dose	Biological: TIN816 70 mg lyophilisate powder; Recombinant human CD39 enzyme
Placebo Comparator: Placebo; 0.9% sterile sodium chloride solution administered as an intravenous dose	Other: Placebo; 0.9% sterile sodium chloride solution

Outcome Measures

Primary Outcome Measures :

1. CMax:The maximum (peak) observed serum drug concentration [ Time Frame: Baseline day 1, day 2, day 3, day 5, day 8, day 14, day 30, day 60 and day 90 ]
   To characterize the pharmacokinetic (PK) profile of TIN816 IV infusion
2. AUClast:The AUC from time zero to the last measurable concentration sampling time (tlast) (mass × time × volume-1) [ Time Frame: Baseline day 1, day 2, day 3, day 5, day 8, day 14, day 30, day 60 and day 90 ]
   To characterize the pharmacokinetic (PK) profile of TIN816 IV infusion
3. AUCinf: The AUC from time zero to infinity [ Time Frame: Baseline day 1, day 2, day 3, day 5, day 8, day 14, day 30, day 60 and day 90 ]
   To characterize the pharmacokinetic (PK) profile of TIN816 IV infusion
4. Tmax: - Time to reach observed maximum drug concentration following TIN816 administration [ Time Frame: Baseline day 1, day 2, day 3, day 5, day 8, day 14, day 30, day 60 and day 90 ]
   To characterize the pharmacokinetic (PK) profile of TIN816 IV infusion
5. T1/2: Terminal half-life [ Time Frame: Baseline day 1, day 2, day 3, day 5, day 8, day 14, day 30, day 60 and day 90 ]
   To characterize the pharmacokinetic (PK) profile of TIN816 IV infusion
6. CL: - Total clearance of drug from serum after intravascular administration [ Time Frame: Baseline day 1, day 2, day 3, day 5, day 8, day 14, day 30, day 60 and day 90 ]
   To characterize the pharmacokinetic (PK) profile of TIN816 IV infusion
7. Vz: Volume of distribution from a systemic dose [ Time Frame: Baseline day 1, day 2, day 3, day 5, day 8, day 14, day 30, day 60 and day 90 ]
   To characterize the pharmacokinetic (PK) profile of TIN816 IV infusion

Secondary Outcome Measures :

1. Number of participants with treatment emergent adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: Baseline up to 90 days ]
   Number of participants with AEs/SAEs as measures of safety and tolerability.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 85 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Signed informed consent must be obtained prior to participation in the study.
2. ≥ 18 and ≤ 85 years of age.
3. Admitted to ICU or intermediate/HDU.

4. Diagnosis of sepsis according to criteria defined by The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) based on:

   Suspected or confirmed infection SOFA score of 2 or more (excluding renal component)

5. Diagnosis of AKI Stage 1 or greater per the following criterion at randomization :

An absolute increase in serum or plasma creatinine (CR) by ≥0.3 mg/dL (≥26.5 µmol/L) within 48 hours or presumed to have occurred in the previous 48 hours as compared to the reference creatinine baseline.

For hospital-acquired AKI, a stable serum creatinine obtained in the hospital prior to AKI should be used as reference baseline, otherwise, baseline serum creatinine in the following order of preference:

Median value within 3 months of the hospital admission. If not available:

Median value between 3 and 6 months prior to hospital admission. If not available:

At hospital admission.

Exclusion criteria

1. Not expected to survive for 24 hours.
2. Not expected to survive for 30 days due to medical conditions other than SA-AKI.
3. History of CKD with a documented estimated GFR <45 ml/min prior to development of AKI.
4. Receiving RRT or a decision has been made to initiate RRT within 24 hours of admission.
5. Weight is less than 40 kg or more than 125 kg .
6. Has life support limitations (eg, do not resuscitate, do not dialyze, do not intubate).
7. AKI diagnosis according to the AKI inclusion criteria for a period longer than 48 hours prior to study drug administration.
8. Presence of AKI for a period longer than 48 hours prior to study drug administration as suggested by clinical manifestations, e.g., prolonged oliguria or severe renal dysfunction (eg, serum creatinine > 4 mg/dL) on admission without a history of CKD.
9. Evidence of recovery from AKI based on the investigator's clinical judgement prior to randomization.
10. AKI is most likely attributable to causes other than sepsis such as nephrotoxic drugs (Non-steroidal anti-inflammatory drugs (NSAIDs), contrast, aminoglycosides), other medical conditions (e.g. heart failure, liver failure, acute abdominal aortic aneurysm, dissection, renal artery stenosis) or urinary obstruction.
11. Documented (biopsy proven) or suspected history of acute or sub-acute kidney diseases such as rapidly progressive glomerular nephritis (RPGN) and acute interstitial nephritis (AIN).
12. Patients who are post-nephrectomy.
13. Patients who are on dual antiplatelet therapy.
14. Patients who are thrombocytopenic at screening (Platelet count <100,000 microliter) or other high risk for bleeding in the opinion of the investigator.

15. Immunosuppressed patients:

    History of immunodeficiency diseases or known HIV test positive. Is receiving immunosuppressant treatment or is on chronic high doses (high-dose therapy exceeding 2 weeks of treatment) of steroids equivalent to prednisone/prednisolone 0.5 mg/kg/day, including solid organ transplant patients. Patients with septic shock treated with hydrocortisone (e.g., 3 × 100 mg) can be included.

16. Active hepatitis (defined as (a) abnormal liver enzymes (Alanine aminotransferase (ALT), Gamma-glutamyl transferase (GGT), ALP > 3x Upper Limit of Normal (ULN) or (b)) for active hepatitis B or C infection, a positive Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) serology or patients with advanced chronic liver disease, confirmed by a Child-Pugh score of 10-15 (Class C).
17. Acute pancreatitis with no established source of infection.
18. Active hematological malignancy (previous hematological malignancies that are not actively treated are allowable).
19. Burns requiring ICU treatment.
20. Sepsis attributed to confirmed COVID-19.
21. Use of other investigational drugs within 5 half-lives of enrollment within 30 days (e.g., small molecules) / or until the expected pharmacodynamic effect has returned to baseline (e.g., biologics), whichever is longer; or longer if required by local regulations.
22. History of hypersensitivity to the study treatment or its excipients or to drugs of similar chemical classes.
23. Any medical conditions that could significantly increase risk of participants' safety by participating in this study according to investigator's judgement.
24. Women with a positive pregnancy test, pregnancy or breast feeding.
25. Women of child-bearing potential

Contacts and Locations

Contacts

Contact: Novartis Pharmaceuticals; +41613241111; novartis.email@novartis.com

Contact: Novartis Pharmaceuticals

Locations

Belgium

Novartis Investigative Site; Recruiting

Genk, Belgium, 3600

Novartis Investigative Site; Recruiting

Ottignies, Belgium, 1340

France

Novartis Investigative Site; Recruiting

Paris, France, 75010

Novartis Investigative Site; Recruiting

Strasbourg Cedex, France, 67091

Novartis Investigative Site; Recruiting

Toulouse Cedex 4, France, 31054

Germany

Novartis Investigative Site; Recruiting

Kiel, Germany, 24105

Novartis Investigative Site; Recruiting

Mainz, Germany, 55131

Hungary

Novartis Investigative Site; Recruiting

Budapest, Pest Megye, Hungary, 1134

Novartis Investigative Site; Recruiting

Debrecen, Hungary, 4032

Spain

Novartis Investigative Site; Recruiting

Hospitalet de Llobregat, Barcelona, Spain, 08907

Novartis Investigative Site; Recruiting

Madrid, Spain, 28046

Novartis Investigative Site; Recruiting

Valencia, Spain, 46026

Sponsors and Collaborators

Novartis Pharmaceuticals

More Information

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT05507437
• Other Study ID Numbers: CTIN816B12201; 2022-000887-23 ( EudraCT Number )
• First Posted: August 19, 2022
• Last Update Posted: May 22, 2023
• Last Verified: May 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

Sepsis; acute kidney injury; intensive care; therapy

Additional relevant MeSH terms:

Sepsis; Toxemia; Acute Kidney Injury; Wounds and Injuries; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases